WHO estimates that there are currently more than 30 million people living with HIV/AIDS and there is a great need to develop a safe and effective therapy that requires short-term intervention and long-term control of viral replication. The overall goal of this proposal is to evaluate the safety and therapeutic potential of in vivo blockade of the inhibitory receptor Programmed Death-1 (PD-1) as a novel therapy to control HIV/AIDS using a SIV/macaque model. Our hypothesis is that blockade of interactions between PD-1 and its ligands can provide therapeutic benefit by eliciting cellular and humoral immunity capable of providing better viral control than the functionally limited T cells and Ab responses characteristic of chronic HIV/SIV infections. We recently demonstrated that PD-1 blockade during the chronic SIV infection (in vivo blockade) is safe, restores the function of anti-viral cellular and humoral immunity, and prolongs survival. These results clearly demonstrated that the PD-1: PDL inhibitory pathway is operational during chronic HIV/SIV infection and strongly suggested that in vivo blockade of PD- 1:PDL pathway might represent a new and powerful therapy for the control of HIV/AIDS. Our recent studies in mice using chronic LCMV infection demonstrated that in vivo PD-1 blockade synergizes with vaccination and elicits highly functional anti-viral CD8 T cell responses and enhances the control of LCMV infection. Highly functional anti-viral cellular and humoral responses are critical for the control of HIV/SIV infections. In this proposal we will test the safety and therapeutic potential of in vivo PD-1 blockade in combination with vaccination in SIV- infected macaques. We hypothesize that combining PD-1 blockade with anti-retroviral therapy (ART) and vaccination will further improve the efficacy of in vivo PD-1 blockade by inducing a robust polyfunctional anti-viral cellular and humoral immunity that is capable of controlling the reemerging viremia following treatment interruption. The vaccine we will use is a SIV239 DNA/MVA vaccine. This vaccine elicits high frequencies of CD8 and CD4 T cells in uninfected macaques. Blocking Ab will be administered prior to or during vaccination. Correlations will be conducted to identify immune responses that are critical for viral control.Our goal is to reduce the set point viremia at least by 50-100 fold. Studies in HIV-infected humans demonstrate that a 10 fold reduction in plasma viremia reduces the death rate from 50% to 5% and prolongs the survival time from less than 5 years to greater than 10 years. If successful, this therapy would potentially improve the health of more than 30 million HIV-infected people across the world. PUBLIC HEALTH RELEVANCE: WHO estimates that there are currently 40 million people living with HIV/AIDS. Introduction of highly active anti-retroviral therapy (HAART) has successfully prolonged the lives of infected individuals. One of the major limitations of HAART is that discontinuation of HAART results in rapid rebound of viremia as a result individuals on HAART need to take these drugs for the rest of their life. The other limitations of HAART include toxicity, the need for rigorous adherence to therapy and the emergence of drug resistant viruses. Thus, there is a great need to develop a safe and effective therapy that requires short-term intervention and long-term control of viral replication. The goal of this proposal is to develop a novel treatment approach for HIV/AIDS that generates very high levels of anti-viral killer cells and antibody responses by blocking the programmed Death-1 (PD-1) inhibitory pathway.